Browsing by Subject "Fluoxetine"

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  • Llach Pou, Maria (Helsingin yliopisto, 2019)
    Parvalbumin (PV) interneurons are GABAergic inhibitory neurons that shape neuronal network activity and plasticity. They are involved in both developmental and adult plasticity and have recently been divided into subpopulations that differ in birthdate, intrinsic properties and are involved in different types of learning; while late born PV neurons, expressing low levels of PV, are required for the acquisition of new information, early born PV neurons, expressing high levels of PV, are involved in the consolidation of the information. PV cells can be enwrapped with perineuronal nets (PNNs), an extracellular matrix structure that stabilizes synapses and indicates a mature state of the cell. The development of PNNs correlates with the closure of critical period of plasticity in development, and the enzymatic removal in adulthood can reopen those periods. Similarly, antidepressants like fluoxetine have been proven to reopen critical periods of plasticity in adulthood (iPlasticity) and decrease PNN structures in PV cells. However, whether the effect of fluoxetine is restricted to a subpopulation of PV interneurons is unknown. In addition, no previous studies have yet investigated the maturity state of the PV subpopulation by analyzing its PNN structures. In this thesis we aimed to elucidate differences in the maturity state of the subpopulations and the fluoxetine effect in those. To do that, we treated a cohort of adult mice with a chronic fluoxetine treatment previously reported to be capable of the reopening of critical periods. Following, we performed an immunohistochemistry analysis to detect PV and PNN levels in the CA3b hippocampal area. In addition, our mice line expressed TdTomato (TdT) in PV cells which allowed a more sensitive detection of PV neurons. After imaging the slices with a confocal microscope, we analyzed the PV and PNN intensity both by manual counting and with a semi-automatic macro script in ImageJ software that we developed and validated. The PV intensity of control mice was used to divide the cells in two groups; low PV and high PV expressing cells. PNNs in those subpopulations in both the control and fluoxetine treated group were analyzed and statistically compared. The low PV subpopulation showed a significantly low PNN intensity compared to the high PV subpopulation, indication a plastic or immature low PV subpopulation and a mature or consolidated high PV subpopulation. Interestingly, fluoxetine selectively decreased the PNN structures in the high PV subpopulation, by bringing the PNN intensity to comparable levels found in the low PV network. No effect of fluoxetine in the low PV network was detected. Fluoxetine induced a change towards a plastic state in the network believed to be involved in memory consolidation by decreasing its PNNs structures. This discovery gives new insights on the understanding of antidepressant plastic actions, suggesting that a chance for strong memories to change could be facilitated with the drug, and explain the antidepressant’s effects when combined with psychotherapy. However, supplementary experiments to compare and define PV subpopulations and a confirmation of the selective effect of fluoxetine are needed to confirm the preliminary hypothesis suggested by our data.
  • Popova, Dina; Castren, Eero; Taira, Tomi (2017)
    Recent studies demonstrate that chronic administration of the widely used antidepressant fluoxetine (FLX) promotes neurogenesis, synaptogenesis and synaptic plasticity in the adult hippocampus, cortex and amygdala. However, the mechanisms underlying these effects and how are they related to the clinical antidepressant efficacy are still poorly understood. We show here that chronic FLX administration decreases hippocampus-associated neophobia in naive mice. In parallel, electrophysiological recordings in hippocampal CA3-CA1 circuitry revealed that the FLX treatment resulted in increased short and long-term plasticity likely attributed to changes in presynaptic function. These changes were accompanied by enhancement in the expression of proteins related to vesicular trafficking and release, namely synaptophysin, synaptotagmin 1, MUNC 18 and syntaxin 1. Thus, chronic FLX administration is associated with enhanced synaptic dynamics atypical of mature CA1 synapses, elevated hippocampal plasticity, improved hippocampus-dependent behavior as well as altered expression of synaptic proteins regulating neurotransmitter trafficking and release. The results support the idea that antidepressants can promote neuronal plasticity and show that they can increase the functional dynamic range and information processing in synaptic circuitries. (C) 2017 Elsevier Ltd. All rights reserved.
  • Popova, Dina; Agustsdottir, Arna; Lindholm, Jesse; Mazulis, Warns; Akamine, Yumiko; Castren, Eero; Karpova, Nina N. (2014)
  • Antila, Hanna (Helsingfors universitet, 2012)
    Tissue plasminogen activator (tPA) is a serine protease that cleaves the inactive plasminogen to a broad-spectrum protease plasmin. Plasmin is involved in the degradation of blood clots by breaking down the fibrin network. In addition to it's role in the fibrinolytic system, tPA participates in the functions of the central nervous system. tPA is expressed in several brain areas and has been shown to be involved in neuronal plasticity. tPA's effects on brain plasticity are mediated in part via degradation of extracellular matrix proteins, but mainly via processing of brain-derived neurotrophic factor (BDNF). Plasmin cleaves pro-BDNF into BDNF that serves as primary endogenous ligand for TrkB neurotrophin receptor. TrkB signalling is strongly associated with the regulation of neuronal plasticity such as neurogenesis, synaptogenesis and long-term potentiation (LTP). On the contrary, pro-BDNF binds and activates p75 neurotrophin receptor that regulates many distinct, even opposite, effects on neuronal plasticity such as long-term depression and synapse refraction. Enhancement of brain plasticity is considered to be important for the therapeutic effects of antidepressant drugs and this is at least partially mediated via BDNF. Antidepressants activate TrkB receptors and increase BDNF protein levels in the rodent brain but the mechanism behind this remains obscure. Given that tPA is an important factor in the processing of BDNF, it is a possible mediator for antidepressants' neurotrophic effects. The effects of antidepressants on tPA activity have been previously studied only in the blood circulatory system. The aim of the experimental part of this Master's thesis was to examine the effects of antidepressant fluoxetine on tPA activity and protein levels in mouse hippocampus. Also the effects of fluoxetine on BDNF-TrkB signalling were studied. Fluoxetine was administered to mice acutely (30 mg/kg, i.p., 1 h) and chronically (0,08 mg/ml in drinking water, 3 weeks). tPA activity was studied using SDS-PAGE - and in situzymographies. TrkB activation, tPA and BDNF protein levels were measured using western blot. BDNF protein levels were also examined with ELISA method. No changes in tPA activity were found after acute fluoxetine treatment. In line with this result is the observation that also the BDNF levels remained unchanged. However, TrkB receptor activity was increased in fluoxetine treated mice. It seems possible that BDNF is not involved in the TrkB activation caused by acute fluoxetine treatment. Chronic fluoxetine treatment caused a significant increase in the BDNF protein levels compared to water-drinking control mice. This was not, however, associated with significant changes in TrkB activity. No changes in tPA activity were observed, which suggests that tPA is not involved in the increase of BDNF levels after chronic fluoxetine treatment. Interestingly, tPA antibody detected three distinct proteins in western blot of whose levels acute fluoxetine treatment regulated. However, more studies are needed to identify these proteins and to reveal the significance of such an effect of fluoxetine. According to this study, neither acute nor chronic fluoxetine treatment affects tPA activity in mouse hippocampus. However, environmental enrichment has been shown to enhance tPA activity and produce similar neurotrophic effects as chronic fluoxetine treatment. Therefore the result of this study concerning effect of chronic antidepressant treatment on tPA activity should be verified.
  • Viikki, Merja; Leinonen, Esa; Koponen, Hannu (2020)
    Masennuslääkkeitä joudutaan vaihtamaan puutteellisen vasteen ja haittavaikutusten vuoksi. Vaihtotapa valitaan yksilöllisesti ja potilaan vointia tulee seurata vaihdon aikana.